Mannich acetaldehyde

Mannich has prepared arecaidine aldehyde (IV) by allowing a mixture of formaldehyde, acetaldehyde and methylamine hydrochloride to stand at 70° and pK 3. Some dialdehyde, MeN(CH2. CHa. CHO)2, is formed and this by loss of water produces arecaidine aldehyde. The latter is, converted into arecoline by the VVohl and Johnson process described above. 

Optimization of the previously reported Mannich-type reaction of trimethyl (pent-2-en-3-yloxy)silane with the sulfone Is derived from phenyl acetaldehyde (Table 5, entry 11) led to the corresponding (3-amino ketone in a good yield with moderate diastereoselectivity (2 mol% Bi(0Tf)3-4H20, yield = 84%, 24v/24v syn/anti = 72 28) (Scheme 8). Reduction of the major diastereoisomer 24v with lithium tri-ferf-butoxyaluminohydride afforded 25 as the only one diastereoisomer. Further cyclization of the latter with NaH afforded 4-benzyl-6-ethyl-5-methyl-l,3-oxazinan-2-one 26. The relative configuration of the six-membered carbamate was established as cis-cis by NMR analysis. 

Ecteinascidin 743 262 (Scheme 12.37) represents a powerful antitumor agent, which has been submitted to clinical trial. This complex polyazacydic, polyaromatic compound was isolated from the marine tunicate, Ecteinascidia turbinate [131]. A total synthesis of this natural product, which featured an Ugi four-component reaction as pivotal step, was recently reported by Fukuyama and co-workers [132]. The highly decorated phenylglycinol 263 was obtained via an asymmetric Mannich-type reaction [133], and was engaged in a multicomponent condensation process involving the protected amino acid 264, p-methoxyphenyl isocyanide 265 and acetaldehyde to afford dipeptide 266 in high yield. This com-... 

It is worthy of note that - similarly to the proline catalyzed aldol reaction - the Mannich reaction can also be extended to an enantio- and diastereoselective process in which two stereogenic centers are formed in one step, although using non-chiral starting materials (Scheme 5.16) [22, 23, 26, 27, 28]. In these reactions substituted acetone or acetaldehyde derivatives, rather than acetone, serve as donor. In contrast with the anti diastereoselectivity observed for the aldol reaction (Section 6.2.1.2), the proline-catalyzed Mannich reaction furnishes products with syn diastereoselectivity [23]. A proline-derived catalyst, which led to the formation of anti Mannich products has, however, been found by the Barbas group [29]. 

The similarity between mechanisms of reactions between proline- and 2-deoxy-ribose-5-phosphate aldolase-catalyzed direct asymmetric aldol reactions with acetaldehyde suggests that a chiral amine would be able to catalyze stereoselective reactions via C-H activation of unmodified aldehydes, which could add to different electrophiles such as imines [36, 37]. In fact, proline is able to mediate the direct catalytic asymmetric Mannich reaction with unmodified aldehydes as nucleophiles [38]. The first proline-catalyzed direct asymmetric Mannich-type reaction between aldehydes and N-PMP protected a-ethyl glyoxylate proceeds with excellent chemo-, diastereo-, and enantioselectivity (Eq. 9). 

F 2-(thiophenyl)vinyl diastereoselective radical acetaldehyde Mannich equivalent... 

A novel Mannich reaction between A -alkoxycarbonylpyrroles 739, formaldehyde, and primary amine hydrochlorides catalyzed by Y(OTf)3 gave a monoaminoalkylation product 741 some times in good yield (14-81%) in aqueous media (Scheme 146) <2001TL461>. When formaldehyde was replaced by acetaldehyde or benzaldehyde, no reaction occurred. There was no formation of the 2,7-diazabicyclo[2.2.1]hept-5-ene 740 (through the aza-Diels-Alder reaction of an N-protected pyrrole with an aldehyde and amine salts by catalysis with triflate). 

Several 4-piperidone syntheses are based on the addition of a primary amine to a divinyl ketone and methods for the preparation of l,2,5-trimethyl-4-piperidone (the precursor of the promedols) and the 2,3-dimethyl analog by this means are shown (Schemes 7.2 and 7.3). 3,5-Dimethyl-4-piperidone is prepared on a similar basis/41 while the 2,6-dimethyl ketone is made either by a Mannich procedure from dimethyl acetonedicarboxylate and acetaldehyde (leading to c-t mixtures)(26) or by catalytic reduction of l,2,6-trimethyl-4(lH)-pyridone (37) and oxidation of the resultant 4-piperidinols, giving a cis product.(58)... 

A diastereoselective formal addition of a 7ra i-2-(phenylthio)vmyl moiety to a-hydroxyhydrazones through a radical pathway is shown in Scheme 2.29. To overcome the lack of a viable intermolecular vinyl radical addition to C=N double bonds, not to mention a reaction proceeding with stereocontrol, this procedure employs a temporary silicon tether, which is used to hold the alkyne unit in place so that the vinyl radical addition could proceed intramolecularly. Thus, intermolecular addition of PhS" to the alkyne moiety in the chiral alkyne 161 leads to vinyl radical 163, which cyclizes in a 5-exo fashion, according to the Beckwith-Houk predictions, to give aminyl radical 164 with an a 7z-arrangement between the ether and the amino group. Radical reduction and removal of the silicon tether without prior isolation of the end product of the radical cyclization cascade, 165, yields the a-amino alcohol 162. This strategy, which could also be applied to the diastereoselective synthesis of polyhydroxylated amines (not shown), can be considered as synthetic equivalent of an acetaldehyde Mannich reaction with acyclic stereocontrol. 

The Mannich reaction of a ketone, an amine, and an aldehyde is one of the few three-component reactions in organic chemistry. Cyclohexanone, for example, reacts with dimethyJamine and acetaldehyde to yield an amino ketone ... 

Xiao, H.-M., Ling, Y., Zhai, Y.-F., Li, Y.-M. Theoretical studies on the mechanism of Mannich reaction involving iminium salt as potential Mannich reagent. Use of acetaldehyde as pseudo-acid component. Chemical Research in Chinese Universities 1997,13, 324-329. 

The loss of acetaldehyde from voacristine (143) when it was heated in acetic acid may well proceed by way of (144), produced by a reverse Mannich reaction cf. Scheme 28) note that (144) is an intermediate of the type necessary for the conversion of an iboga type into (132) by an ionic route. 4,20-Dehydro voacangine (145) was also produced in this reaction. 

To facilitate the use of p-amino-aldehydes or -alcohols, obtained through asymmetric Mannich reactions, List et al. provided a procedure to use N-Boc-protected, preformed imines (21, 22) (Scheme 5.13a). While this method requires the formation of the imines, it provides products that can be deprotected under mild conditions, as compared to the widely used and robust PMB-protection in these reactions. Even acetaldehyde is applicable as aldehyde source (Scheme 5.13b). The p-amino-aldehydes (23, 24) obtained from this transformation are extremely valuable building blocks in organic synthesis, making this discovery one of the most useful applications of proline catalysis to date. 

Prolinol silyl ether catalysts were also able to control the Mannich reaction of acetaldehyde. Xu and coworkers utilised Michael adducts of aldehydes with nitroalkenes in the subsequent Mannich-type reaction with imines followed by cyclisation. Highly substituted chiral piperidines were formed. Suitable imines for organocatalytic Mannich reactions can also be generated in situ from amido sulfones (Scheme 8.34). ... 

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